DESCRIPTION (adapted from applicant's summary) Paired helical filaments (PHFs), the building blocks of Alzheimer's disease (AD) neurofibrillary tangles (NFTs) are formed from hyperphosphorylated brain tau known as PHFtau. Recent evidence suggests that an imbalance between kinase and phosphatase activities that co-ordinately regulate the phosphorylation state of tau and the stability of the neuronal cytoskeleton in tangle bearing neurons could lead to the destabilization of the cytoskeletal network. This could lead to the disruption of axonal transport, the dying back of the axon and the dysfunction and degeneration of neurons. However, the kinases and phosphatases that regulate the phosphorylation state of tau and the stability of the cytoskeleton in intact neurons have not been identified. Furthermore, it is well known that the activities of these kinases and phosphatases are regulated by exogenous factors in multiple signal transduction pathways. Thus, the goals of this renewal application are to: 1) Identify the kinases and phosphatases that regulate the phosphorylation state of tau and the stability of the neurofilament and microtubule networks in cultured human neurons. 2) Determine how these kinases and phosphatases are regulated by multiple signal transduction pathways. Successful completion of the proposed studies could lead to an understanding of the sequence of events that lead to the hyperphosphorylation of tau, the formation of PHFs and the destabilization of the neuronal cytoskeleton in AD.